In order to assess the effects of specific genes on premalignant progression in vivo, we have generated transgenic mice in which the tetracycline regulatable transactivators tTA and rTA are targeted to the epidermis with a keratin 5 promoter. The efficacy of the these lines as transactivators in vivo has been demonstrated by crossing them with a transgenic line expressing a tetO/beta-galactosidase transgene. Both systemic and topical doxycycline can suppress or activate expression of beta-galactosidase in the double transgenic mice. We have generated several tetO transgenics with different target genes including an oncogenic c-ras and a constitutively active TGFb in order to regulate their expression at specific stages of carcinogenesis. In mice containing both the BK5/tTA and tetOTGFb1 transgenes, high levels of expression of TGFb1 produces an embryonic lethal phenotype. Partial suppression with suboptimal levels of doxycycline generates full term but nonviable mice. The neonatal lethal phenotype is characterized by runting, hypoplastic epidermis and atrophy of the hair follicles. Complete suppression of TGFb1 expression allows for normal embryonic development. However, if double transgenic mice are removed from doxycycline after weaning, the mice undergo progressive alopecia at the onset of the second hair cycle. Associated with the alopecia is significant follicular hyperplasia and focal inflammation. If the mice are returned to doxycycline, hair regrows within 2-3 weeks. This conditional system will be used to induce TGFb1 at different stages of carcinogenesis inorder to explore the molecular basis of its dual action in tumor development